! PROJECT SUMMARY The destruction of the World Trade Center Towers (WTC) on September 11, 2001 resulted in the massive release of dust, gas, and fumes with potential acute and chronic inhalation for community members (?Survivors?). The presence and persistence of lower respiratory symptoms (LRS) in Survivors and Responders is now well-documented. Although often managed as asthma, findings associated with LRS include abnormal small airways and alveoli (i.e. distal lung units) identified in lung pathologic specimens and physiologic measurements. These studies suggest that inhalation of toxic agents can produce abnormalities in the distal lung unit that result in lower respiratory symptoms. Our recent preliminary studies suggest that there is incomplete improvement in spirometry and small airway measurements over time and symptoms, particularly dyspnea on exertion, persist despite therapy with high dose inhaled corticosteroid and long acting ?2-agonist. The involvement of the distal lung units and the incomplete reversibility of symptoms with therapy are similar to findings in COPD. Thus, we can call this the ?small Airway Chronic Obstruction Syndrome? (sACOS). The persistence of LRS and the resulting functional impairment makes it imperative to understand the underlying physiologic and biologic mechanisms in order to improve therapy. Distal lung unit abnormalities can be revealed / exaggerated during rapid breathing (as during exercise), and result in expiratory flow limitation and/or dynamic hyperinflation providing a potential mechanism for exertional dyspnea. To understand the persistent LRS, we propose to: 1) relate dyspnea to measures of functional abnormalities in distal lung units at rest and during exercise; 2) since responses to ICS/LABA are incomplete, determine whether residual reversibility can be elicited with an anti muscarinic agent; and 3) identify biologic markers associated with LRS that can lead to new interventions. Our overarching hypothesis is that persistent LRS in WTC ?Survivors? are associated with abnormal small airways/distal lung units whose dysfunction is amplified during exercise and are associated with biologic correlates of inflammation and remodeling. This hypothesis will be evaluated with the following specific aims: Specific Aim 1: Compared with healthy controls, do ?Survivors? with persistent LRS have functional abnormalities in their distal lung units that are revealed during exercise? Specific Aim 2: Compared to healthy controls, do ?Survivors? with LRS have lung and systemic inflammation associated with markers of remodeling? The present proposal will address a knowledge gap in inhalational lung injury specifically for WTC ?Survivors.? Understanding the underlying processes of LRS, particularly dyspnea on exertion, has implications for management of WTC exposed populations and wider implications for other inhalation injuries in which distal lung units may be involved